Rivastigmine

Pronunciation

(ri va STIG meen)

U.S. Brand Names

Exelon®

Synonyms

ENA 713; Rivastigmine Tartrate; SDZ ENA 713

Generic Available

Canadian Brand Names

Exelon®

Use

Mild to moderate dementia from Alzheimer's disease

Pregnancy Risk Factor

Pregnancy Implications

There are no adequate and well-controlled studies in pregnant women. Should be used only if the benefit outweighs the potential risk to the fetus.

Lactation

Excretion in breast milk unknown/use caution

Contraindications

Hypersensitivity to rivastigmine, other carbamate derivatives, or any component of the formulation

Warnings/Precautions

Significant nausea, vomiting, anorexia, and weight loss are associated with use; occurs more frequently in women and during the titration phase. If treatment is interrupted for more than several days, reinstate at the lowest daily dose. Use caution in patients with a history of peptic ulcer disease or concurrent NSAID use. Caution in patients undergoing anesthesia who will receive succinylcholine-type muscle relaxation, patients with sick sinus syndrome, bradycardia or supraventricular conduction conditions, urinary obstruction, seizure disorders, or pulmonary conditions such as asthma or COPD. There are no trials evaluating the safety and efficacy in children.

Adverse Reactions

>10%:

Central nervous system: Dizziness (21%), headache (17%)

Gastrointestinal: Nausea (47%), vomiting (31%), diarrhea (19%), anorexia (17%), abdominal pain (13%)

2% to 10%:

Cardiovascular: Syncope (3%), hypertension (3%)

Central nervous system: Fatigue (9%), insomnia (9%), confusion (8%), depression (6%), anxiety (5%), malaise (5%), somnolence (5%), hallucinations (4%), aggressiveness (3%)

Gastrointestinal: Dyspepsia (9%), constipation (5%), flatulence (4%), weight loss (3%), eructation (2%)

Genitourinary: Urinary tract infection (7%)

Neuromuscular & skeletal: Weakness (6%), tremor (4%)

Respiratory: Rhinitis (4%)

Miscellaneous: Increased diaphoresis (4%), flu-like syndrome (3%)

>2% (but frequency equal to placebo): Chest pain, peripheral edema, vertigo, back pain, arthralgia, pain, bone fracture, agitation, nervousness, delusion, paranoid reaction, upper respiratory tract infection, infection, cough, pharyngitis, bronchitis, rash, urinary incontinence.

<2% (Limited to important or life-threatening symptoms; reactions may be at a similar frequency to placebo): Fever, edema, allergy, periorbital or facial edema, hypothermia, hypotension, postural hypotension, cardiac failure, ataxia, convulsions, apraxia, aphasia, dysphonia, hyperkinesia, hypertonia, hypokinesia, migraine, neuralgia, peripheral neuropathy, hypothyroidism, peptic ulcer, gastroesophageal reflux, GI hemorrhage, intestinal obstruction, pancreatitis, colitis, atrial fibrillation, bradycardia, AV block, bundle branch block, sick sinus syndrome, cardiac arrest, supraventricular tachycardia, tachycardia, abnormal hepatic function, cholecystitis, dehydration, arthritis, angina pectoris, MI, epistaxis, hematoma, thrombocytopenia, purpura, delirium, emotional lability, psychosis, anemia, bronchospasm, apnea, rash (maculopapular, eczema, bullous, exfoliative, psoriaform, erythematous), urticaria, acute renal failure, peripheral ischemia, pulmonary embolism, thrombosis, thrombophlebitis, intracranial hemorrhage, conjunctival hemorrhage, diplopia, glaucoma, lymphadenopathy, leukocytosis.

Postmarketing and/or case reports: Stevens-Johnson syndrome, severe vomiting with esophageal rupture (following inappropriate reinitiation of dose)

Overdosage/Toxicology

In cases of asymptomatic overdoses, rivastigmine should be held for 24 hours. Cholinergic crisis, caused by significant acetylcholinesterase inhibition, is characterized by severe nausea, vomiting, salivation, sweating, bradycardia, hypotension, respiratory depression, collapse, and convulsions. Treatment is supportive and symptomatic. Dialysis would not be helpful.

Drug Interactions

Anticholinergics: Effects may be reduced with rivastigmine

Beta-blockers without ISA activity: May increase risk of bradycardia

Calcium channel blockers (diltiazem or verapamil): May increase risk of bradycardia

Cholinergic agonists: Effects may be increased with rivastigmine

Cigarette use increases the clearance of rivastigmine by 23%

Digoxin: Increased risk of bradycardia with concurrent use

Neuromuscular blockers: Depolarizing neuromuscular blocking agents effects may be increased with rivastigmine

NSAIDs: Although not seen in clinical studies, patients may be at increased risk for peptic ulcers or gastrointestinal bleeding with concomitant use; monitor

Ethanol/Nutrition/Herb Interactions

Cigarette use: Increases the clearance of rivastigmine by 23%.

Ethanol: Avoid ethanol (due to risk of sedation; may increase GI irritation).

Food: Food delays absorption by 90 minutes, lowers Cmax by 30% and increases AUC by 30%.

Stability

Store below 25°C (77°F); store solution in an upright position and protect from freezing

Mechanism of Action

A deficiency of cortical acetylcholine is thought to account for some of the symptoms of Alzheimer's disease; rivastigmine increases acetylcholine in the central nervous system through reversible inhibition of its hydrolysis by cholinesterase

Pharmacodynamics/Kinetics

Absorption: Fasting: Rapid and complete within 1 hour

Distribution: Vd: 1.8-2.7 L/kg

Protein binding: 40%

Metabolism: Extensively via cholinesterase-mediated hydrolysis in the brain; metabolite undergoes N-demethylation and/or sulfate conjugation hepatically; CYP minimally involved; linear kinetics at 3 mg twice daily, but nonlinear at higher doses

Bioavailability: 40%

Half-life elimination: 1.5 hours

Time to peak: 1 hour

Excretion: Urine (97% as metabolites); feces (0.4%)

Dosage

Adults: Mild to moderate Alzheimer's dementia: Oral: Initial: 1.5 mg twice daily to start; if dose is tolerated for at least 2 weeks then it may be increased to 3 mg twice daily; increases to 4.5 mg twice daily and 6 mg twice daily should only be attempted after at least 2 weeks at the previous dose; maximum dose: 6 mg twice daily. If adverse events such as nausea, vomiting, abdominal pain, or loss of appetite occur, the patient should be instructed to discontinue treatment for several doses then restart at the same or next lower dosage level; antiemetics have been used to control GI symptoms. If treatment is interrupted for longer than several days, restart the treatment at the lowest dose and titrate as previously described.

Elderly: Clearance is significantly lower in patients older than 60 years of age, but dosage adjustments are not recommended. Titrate dose to individual's tolerance.

Dosage adjustment in renal impairment: Dosage adjustments are not recommended, however, titrate the dose to the individual's tolerance.

Dosage adjustment in hepatic impairment: Clearance is significantly reduced in mild to moderately impaired patients. Although dosage adjustments are not recommended, use lowest possible dose and titrate according to individual's tolerance. May consider waiting >2 weeks between dosage adjustments.

Administration

Should be administered with meals (breakfast or dinner). Capsule should be swallowed whole. Liquid form is available for patients who cannot swallow capsules (can be swallowed directly from syringe or mixed with water, milk, or juice). Stir well and drink within 4 hours of mixing.

Monitoring Parameters

Cognitive function at periodic intervals

Dietary Considerations

Should be taken with meals.

Patient Education

This drug is not a cure for Alzheimer's disease, but it may reduce the symptoms. Use as directed; do not increase dose or discontinue without consulting prescriber. Swallow capsule whole with meals (do not crush or chew). Liquid can be swallowed directly from syringe or mixed with water, milk, or juice; stir well and drink within 4 hours of mixing. Maintain adequate hydration (2-3 L/day of fluids) unless instructed to restrict fluid intake. Avoid alcohol. May cause dizziness, drowsiness, or postural hypotension (rise slowly from sitting or lying position and use caution when driving or climbing stairs); vomiting or loss of appetite (small, frequent meals, frequent mouth care, sucking lozenges, or chewing gum may help); diarrhea (buttermilk, boiled milk, or yogurt may help); or constipation (increased exercise, fluids, fruit, or fiber may help); or urinary frequency. Report persistent abdominal discomfort, diarrhea, or constipation; significantly increased salivation, sweating, tearing, or urination; chest pain, palpitations, acute headache; CNS changes (eg, excessive fatigue, agitation, insomnia, dizziness, confusion, aggressiveness, depression); increased muscle, joint, or body pain; vision changes or blurred vision; shortness of breath, coughing, or wheezing; skin rash; or other persistent adverse reactions. Breast-feeding precaution: Consult prescriber if breast-feeding.

Nursing Implications

Educate patient or caregiver about medicine.

Cardiovascular Considerations

Because of the cholinergic activity due to inhibition of acetylcholinesterase, rivastigmine may induce significant bradycardia. Caution is especially indicated in patients with sick sinus syndrome and pre-existing cardiac conduction abnormalities. Interactions with beta-blockers, calcium channel blockers, and digoxin may potentiate bradycardia and may predispose to significant hypotension.

Dental Health: Effects on Dental Treatment

No significant effects or complications reported

Dental Health: Vasoconstrictor/Local Anesthetic Precautions

No information available to require special precautions

Dosage Forms

Capsule: 1.5 mg, 3 mg, 4.5 mg, 6 mg

Solution, oral: 2 mg/mL (120 mL) [contains sodium benzoate]

International Brand Names

Exelon® (AR, AT, AU, BE, BR, CA, CH, CL, CO, CR, CZ, DE, DK, DO, EC, ES, FI, FR, GB, GT, HN, HR, HU, ID, IE, IL, IN, IT, MX, NL, NO, NZ, PA, PL, PT, RO, RU, SE, SG, SI, SV, TH, TR, YU, ZA); Prometax® (ES, IT, PT)

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